4,5-dihydro-1H-pyrazole derivatives having CB1-antagonistic activity

This application is a National Stage application under 35 U.S.C. § 371 of PCT/EP02/10433, filed Sep. 17, 2002, which claims priority from European Patent Application EP 01203850.1, filed Sep. 21, 2001, both of which are hereby incorporated by reference.

The present invention relates to a group of novel 4,5-dihydro-1H-pyrazole derivatives, to methods for the preparation of these compounds, and to pharmaceutical compositions containing one or more of these compounds as an active component.

The above mentioned 4,5-dihydro-1H-pyrazoles are potent cannabinoid (CB 1 ) receptor antagonists with utility for the treatment of diseases connected with disorders of the cannabinoid system.

Cannabinoids are present in the Indian hemp Cannabis sativa and have been used as medicinal agents for centuries (Mechoulam, R. and Feigenbaum, J. J. Prog. Med. Chem. 1987, 24, 159). However, only within the past ten years the research in the cannabinoid area has revealed pivotal information on cannabinoid receptors and their (endogenous) agonists and antagonists. The discovery and the subsequent cloning of two different subtypes of Cannabinoid receptors (CB 1 and CB 2 ) stimulated the search for novel cannabinoid receptor antagonists (Munro, S. et al., Nature 1993, 365, 61. Matsuda, L. A. and Bonner, T. I. Cannabinoid Receptors , Pertwee, R. G. Ed. 1995, 117, Academic Press, London). In addition, pharmaceutical companies became interested in the development of cannabinoid drugs for the treatment of diseases connected with disorders of the cannabinoid system (Consroe, P. Neurobiology of Disease 1998, 5, 534. Pop, E. Curr. Opin. In CPNS Investigational Drugs 1999, 1, 587. Greenberg, D. A. Drug News Perspect. 1999, 12, 458. Pertwee, R. G., Progress in Neurobiology 2001, 63, 569). Hitherto, several CB 1 receptor antagonists are known. Sanofi disclosed their diarylpyrazole congeners as selective CB 1 receptor antagonists. A representative example is SR-141716A (Dutta, A. K. et al., Med. Chem. Res. 1994, 5, 54. Lan, R. et al., J. Med. Chem. 1999, 42, 769. Nakamura-Palacios, E. M. et al., CNS Drug Rev. 1999, 5, 43). CP-272871 is a pyrazole derivative, like SR141716A, but less potent and less CB 1 receptor subtype-selective than SR141716A (Meschler, J. P. et al., Pharmacol. 2000, 60, 1315). Aminoalkylindoles have been disclosed as CB 1 receptor antagonists. A representative example is Iodopravadoline (AM-630), which was introduced in 1995. AM-630 is a moderately active CB 1 receptor antagonist, but sometimes behaves as a weak partial agonist (Hosohata, K. et al., Life Sc. 1997, 61, PL115). Researchers from Eli Lilly described aryl-aroyl substituted benzofurans as selective CB 1 receptor antagonists (e.g. LY-320135) (Felder, C. C. et al., J. Pharmacol. Exp. Ther. 1998, 284, 291). 3-Alkyl-5,5′-diphenylimidazolidinediones were described as cannabinoid receptor ligands, which were indicated to be cannabinoid antagonists (Kanyonyo, M. et al., Biorg. Med. Chem. Lett. 1999, 9, 2233). Aventis Pharma claimed diarylmethyleneazetidine analogs as CB 1 receptor antagonists (Mignani, S. et al., Patent FR 2783246, 2000 ; Chem. Abstr. 2000, 132, 236982). Tricyclic pyrazoles were claimed by Sanofi-Synthelabo as CB 1 antagonists (Barth, F. et al., Chem. Abstr 2001, 134, 340504). Interestingly, many CB 1 receptor antagonists have been reported to behave as inverse agonists in vitro (Landsman, R. S. et al., Eur. J. Pharmacol. 1997, 334, R1). Reviews provide a nice overview of the cannabinoid research area (Mechoulam, R. et al., Prog. Med. Chem. 1998, 35, 199. Lambert, D. M. Curr. Med. Chem. 1999, 6, 635. Mechoulam, R. et al., Eur. J. Pharmacol. 1998, 359, 1. Williamson, E. M. and Evans, F. J. Drugs 2000, 60, 1303. Pertwee, R. G. Addiction Biology 2000, 5, 37. Robson, P. Br. J. Psychiatry 2001, 178, 107. Pertwee, R. G. Prog. Neurobiol. 2001, 63, 569. Goya, P; Jagerovic, N. Exp. Opin. Ther. Patents 2000, 10, 1529. Pertwee, R. G. Gut 2001, 48, 859).

It has now surprisingly been found that potent and selective antagonism of cannabinoid-CB 1 receptors is present in the novel 4,5-dihydro-1H-pyrazole derivatives of the formula (I), prodrugs thereof, tautomers thereof and salts thereof

wherein

R and R 1 independently represent phenyl, thienyl or pyridyl which groups may be substituted with 1, 2, 3 or 4 substituents Y, which can be the same or different, from the group C 1-3 -alkyl or alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono- or dialkyl (C 1-2 )-amino, mono- or dialkyl (C 1-2 )-amido, (C 1-3 )-alkyl sulfonyl, dimethylsulfamido, C 1-3 -alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl, or R and/or R 1 represent naphtyl, R 2 represents hydrogen, hydroxy, C 1-3 -alkoxy, acetyloxy or propionyloxy, R 3 represents a hydrogen atom or a branched or unbranched C 1-8 alkyl group or a C 3-7 cycloalkyl group which alkyl group or cycloalkyl group may be substituted with a hydroxy group, R 4 represents a C 2-10 branched or unbranched heteroalkyl group, C 3-8 non-aromatic heterocycloalkyl group or C 4-10 non-aromatic heterocycloalkyl-alkyl group which groups contain one or more heteroatoms from the group (O, N, S) or a —SO 2 — group, which C 2-10 branched or unbranched heteroalkyl group, C 3-8 non-aromatic heterocycloalkyl group or C 4-10 non-aromatic heterocycloalkyl-alkyl group may be substituted with a keto group, trifluoromethyl group, C 1-3 alkyl group, hydroxy, amino, monoalkylamino, or dialkylamino group or a fluoro atom, or R 4 represents an amino, hydroxy, phenoxy or benzyloxy group, or R 4 represents a C 1-8 alkoxy, C 3-8 alkenyl, C 5-8 cycloalkenyl or C 6-9 cycloalkenylalkyl group which groups may contain a sulphur, nitrogen or oxygen atom, a keto group or —SO 2 — group, which alkoxy, alkenyl and cycloalkenyl groups may be substituted with a hydroxy group, a trifluoromethyl group, an amino group, a monoalkylamino group or dialkylamino group or a fluoro atom, or R 4 represents a C 2-5 alkyl group which alkyl group contains a fluoro atom, or R 4 represents an imidazolylalkyl group, benzyl, pyridylmethyl, phenethyl or thienyl group, or R 4 represents a substituted phenyl, benzyl, pyridyl, thienyl, pyridylmethyl or phenethyl group wherein the aromatic rings are substituted with 1, 2 or 3 of the substituents Y, wherein Y has the meaning as indicated above, or when R 3 is H or methyl, R 4 may represent a group NR 6 R 7 wherein R 6 and R 7 are the same or different and represent C 2-4 alkyl, C 2-4 trifluoroalkyl or R 6 represents a methyl group with the proviso that R 7 represents a C 2-4 alkyl group, or R 6 and R 7 —together with the nitrogen atom to which they are bonded—form a saturated or unsaturated heterocyclic moiety having 4 to 8 ring atoms which heterocyclic moiety may contain an oxygen or sulphur atom or a keto group or —SO 2 — group or an additional nitrogen atom, which saturated or unsaturated heterocyclic moiety may be substituted with a C 1-4 alkyl group, or R 3 and R 4 together with the nitrogen atom to which they are bonded form a saturated or unsaturated, monocyclic or bicyclic heterocyclic moiety having 4 to 10 ring atoms, which heterocyclic moiety may contain one or more atoms from the group (O, N, S) or a keto group or —SO 2 — group, which moiety may be substituted with a C 1-4 alkyl, hydroxyalkyl, phenyl, thienyl, pyridyl, amino, monoalkylaminoalkyl, dialkylaminoalkyl, monoalkylamino, dialkylamino, aminoalkyl, azetidinyl, pyrrolidinyl, piperidinyl or hexahydro-1H-azepinyl group, R 5 represents benzyl, phenyl, thienyl or pyridyl which may be substituted with 1, 2, 3 or 4 substituents Y, wherein Y has the meaning as indicated above, which can be the same or different, or R 5 represents C 1-8 branched or unbranched alkyl, C 3-8 alkenyl, C 3-10 cycloalkyl, C 5-10 bicycloalkyl, C 6-10 tricycloalkyl or C 5-8 cycloalkenyl or R 5 represents naphtyl.

At least one centre of chirality is present (at the C 4 position of the 4,5-dihydro-1H-pyrazole moiety) in the compounds of the formula (I). The invention relates both to racemates, mixtures of diastereomers and the individual stereoisomers of the compounds having formula (I). Particular compounds of interest of formula (I) have the absolute stereoconfiguration at the C 4 position of the 4,5-dihydro-1H-pyrazole moiety as represented by formula (1 a ).

The invention also relates both to the E isomer, Z isomer and E/Z mixtures of compounds having formula (I).

The compounds of the invention can be brought into forms suitable for administration by means of usual processes using auxiliary substances and/or liquid or solid carrier materials.

Due to the potent CB 1 antagonistic activity the compounds according to the invention are suitable for use in the treatment of psychiatric disorders such as psychosis, anxiety, depression, attention deficits, memory disorders, cognitive disorders, appetite disorders, obesity, addiction, appetence, drug dependence and neurological disorders such as neurodegenerative disorders, dementia, dystonia, muscle spasticity, tremor, epilepsy, multiple sclerosis, traumatic brain injury, stroke, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease, Tourette's syndrome, cerebral ischaemia, cerebral apoplexy, craniocerebral trauma, stroke, spinal cord injury, neuroinflammatory disorders, plaque sclerosis, viral encephalitis, demyelinisation related disorders, as well as for the treatment of pain disorders, including neuropathic pain disorders, and other diseases involving cannabinoid neurotransmission, including the treatment of septic shock, glaucoma, cancer, diabetes, emesis, nausea, asthma, respiratory diseases, gastrointestinal disorders, gastric ulcers, diarrhoea and cardiovascular disorders.

The affinity of the compounds of the invention for cannabinoid CB 1 receptors was determined using membrane preparations of Chinese hamster ovary (CHO) cells in which the human cannabinoid CB 1 receptor is stably transfected in conjunction with [ 3 H]CP-55,940 as radioligand. After incubation of a freshly prepared cell membrane preparation with the [ 3 H]-ligand, with or without addition of compounds of the invention, separation of bound and free ligand was performed by filtration over glassfiber filters. Radioactivity on the filter was measured by liquid scintillation counting.

The cannabinoid CB 1 antagonistic activity of compounds of the invention was determined by functional studies using CHO cells in which human cannabinoid CB 1 receptors are stably expressed. Adenylyl cyclase was stimulated using forskolin and measured by quantifying the amount of accumulated cyclic AMP. Concomitant activation of CB 1 receptors by CB 1 receptor agonists (e.g. CP-55,940 or (R)-WIN-55,212-2) can attenuate the forskolin-induced accumulation of cAMP in a concentration-dependent manner. This CB 1 receptor-mediated response can be antagonised by CB 1 receptor antagonists such as the compounds of the invention.

Intermediates having formula (II) (see below) can be obtained according to methods known, for example: a) Francotte, E. and Tong, Z. Chem. Abstr. 126, 213598; b) Rempfler, H. and Kunz, W. Chem. Abstr. 113, 40432; c) Rempfler, H. and Kunz, W. Chem. Abstr. 107, 217473.

Intermediates having formula (III) (see below), wherein R 2 represents hydrogen can be obtained according to methods known, for example: a) EP 0021506; b) DE 2529689; c) Grosscurt, A. C. et al., J. Agric. Food Chem. 1979, 27, (2), 406.

Intermediates having formula (III) (see below), wherein R 2 represents a hydroxy group can be obtained by reacting of a compound having formula (II)

with hydrazine or hydrazine hydrate. This reaction is preferably carried out in an organic solvent, for example ethanol, and yields a compound having formula (III)

Suitable synthetic routes for the compounds of the invention are the following:

Synthetic Route A1

Step 1: reaction of a compound having formula (III) with a thioisocyanate derivative having formula (IV),

preferably carried out in an organic solvent, for example acetonitrile. This reaction gives a thiocarboxamide derivative having formula (V), wherein R, R 1 , R 2 and R 5 have the meanings as described above for compound (I).

Step 2: reaction of a compound having formula (V) with a compound R 3 R 4 NH in the presence of a mercury(II) salt, such as for example HgCl 2 , gives a compound having formula (I). This reaction is preferably carried out in an organic solvent, such as for example acetonitrile.

Synthetic Route A2

with a carbamate ester derivative having formula (VI).

wherein R 8 represents a lower alkyl group, for example methyl. This reaction is preferably carried out in an organic solvent, for example 1,4-dioxane, and yields a 4,5-dihydropyrazole-1-carboxamide derivative having formula (VII), wherein R, R 1 , R 2 and R 5 have the meanings as described above for compound (I).

Step 2: reaction, preferably carried out in an inert organic solvent, for example chlorobenzene, of a compound having formula (VII) with a halogenating agent such as PCl 5 , gives a 4,5-dihydropyrazole-1-carboximidoyl halogenide derivative having formula (VIII) wherein R, R 1 , R 2 , R 5 have the meanings as described above for compound (I) and wherein R 9 represents a halogen atom, for example Cl.

Step 3: reaction of a compound having formula (VIII) with a compound R 3 R 4 NH preferably carried out in an inert organic solvent, such as for example dichloromethane gives a compound having formula (I).

Alternatively, compounds R 3 R 4 NH which contain an additional nucleophilic nitrogen atom are reacted with a compound having formula (VIII) in such a way that the abovementioned additional nucleophilic nitrogen atom is protected by a protective group, for example a t-butoxycarbonyl (Boc) group and the like. Subsequent removal of the protective group according to known methods yields a compound having formula (I). (See for example: T. W. Greene and P. G. M. Wuts, “ Protective Groups in Organic Synthesis”, third edition , John Wiley & Sons, Inc., New York, 1999).

Synthetic Route A3

with a dithioimidocarbonic ester derivative having formula (IX).

wherein R 10 represents a C 1-3 alkyl group. This reaction is preferably carried out in an organic solvent, for example acetonitrile or toluene, and yields a carboximidothioic ester derivative having formula (X), wherein R, R 1 , R 2 , R 5 have the meanings as described above for compound (I) and wherein R 10 represents a C 1-3 alkyl group.

Alternatively, a compound having formula (X) can be obtained from the reaction of a compound having formula (V) with a compound R 10 —X, wherein X represents a leaving group such as an iodide group, and R 10 has the meaning as described above for (X).

Step 2: Reaction, preferably carried out in an organic solvent, such as methanol, of a compound having formula (X) with a compound R 3 R 4 NH gives a compound having formula (I).

The preparation of the compounds is illustrated in the following examples.